title: Optimization of pentadentate bispidines as bifunctional chelators for 64Cu positron emission tomography (PET).
abstract: Pentadentate bispidine ligands (3,7-diazabicyclo[3.3.1]nonanes) are optimized for maximum complex stability and facile functionalization with respect to their coupling to biological vector molecules and/or fluorescence markers for PET (positron emission tomography) and multimodal imaging (i.e., PET and optical imaging). The pentadentate ligand with two tertiary amine donors, two p-methoxy substituted pyridines, and one unsubsituted pyridine group is shown to best fulfill important conditions for PET applications, i.e., fast complexation with Cu(II) and high in vivo stability, and this was predicted from the solution chemistry, in particular the Cu(II/I) redox potentials. Also, solvent partition experiments to model the lipophilicity of the Cu(II) complexes indicate that the bis p-methoxy substituted ligand leads to cationic complexes with an appreciable lipophilicity. This is supported by the biodistribution experiments that show that the complex with the p-methoxy substituted ligand is excreted very quickly and primarily via the renal route and therefore is ideally suited for the development of PET tracers with ligands of this type coupled to biomolecules.
authors.affiliation: Anorganisch-Chemisches Institut, Universität Heidelberg, INF 270, D-69120 Heidelberg, Germany. peter.comba@aci.uni-heidelberg.de
authors.forename: Peter
authors.initials: P
authors.lastname: Comba
authors.forename: Sebastian
authors.initials: S
authors.lastname: Hunoldt
authors.forename: Michael
authors.initials: M
authors.lastname: Morgen
authors.forename: Jens
authors.initials: J
authors.lastname: Pietzsch
authors.forename: Holger
authors.initials: H
authors.lastname: Stephan
authors.forename: Hubert
authors.initials: H
authors.lastname: Wadepohl
mesh_terms: D000818:Animals; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000737:chemistry* / Q000378:metabolism; D002614:Chelating Agents / Q000737:chemistry* / Q000378:metabolism; D003301:Copper Radioisotopes / Q000737:chemistry* / Q000378:metabolism; D008958:Models, Molecular; D049268:Positron-Emission Tomography / Q000379:methods; D011725:Pyridines / Q000737:chemistry* / Q000378:metabolism; D019275:Radiopharmaceuticals / Q000737:chemistry* / Q000378:metabolism; D051381:Rats; D011921:Rats, Inbred WKY; D014018:Tissue Distribution
chemical_list: D019086:Bridged Bicyclo Compounds, Heterocyclic; D002614:Chelating Agents; D003301:Copper Radioisotopes; D011725:Pyridines; D019275:Radiopharmaceuticals; C495809:bispidine